There are only two areas to book a hotel in - either downtown between Third Street and the River, or East of the I-240 loop.  If you are thinking about a hotel other than these two areas, you are simply making a mistake.  Beale Street at night is very safe and fun.  Stay east of I-240 if you are here on business, stay downtown if you are visiting. 

If you're just passing through, anything on Goodman Road, either at Hwy 78 or I-55, will do.  It does lie south of the city - indeed, it's over the line in Mississippi - but for those travelers driving through from the south or the north, you'll be close to chain dining or a familiar shopping spot for essentials.